PROJECT SUMMARY Breast cancer (BC) is the second most common cancer diagnosed in American women and the second leading cause of cancer death for women in general. Compared to Caucasian American (CA) women, African American (AA) women display an earlier onset of BC and have a significantly higher mortality rate. While the role of societal factors for the poorer outcome of AA women with BC is well-established, the biological factors that mediate BC racial disparities remain largely unknown. In our preliminary studies, we identified that lipolysis-stimulated lipoprotein receptor (LSR) was expressed at the highest levels in African American BC cells, especially in triple negative BC (TNBC). We also developed a tumor specific anti-LSR antibody, tested multiple small molecules showing high toxicity, and established LSR targeting antibody-drug conjugates (ADCs) construction and evaluation procedures. Our central hypothesis is that the anti-LSR ADCs-based therapy can effectively inhibit TNBC growth with a limited side effect, especially in AA patients. In this study, we propose to develop targeted therapies for curative treatment of AA TNBC. Aim 1, we will examine the expression profile and genetic/epigenetic alterations of LSR in BC tissues between AA and CA patients. We will also assess the differences among the localized, regional and distant tumor stages and the correlation between LSR expression and genetic/epigenetic alteration. Aim 2, we aim to build an effective platform of ADC-based targeted therapies to treat TNBC, and to identify the most efficient anti-LSR ADC strategy by investigating the targeting specificity, anti-TNBC efficacy, anti-LSR mAb-induced suppression of lipid metabolism, and various ADCs-mediated anti- tumor effects. Aim 3, we aim to use our established protocols of maximal tolerated dose, pharmacokinetics, biodistribution and anti-tumor toxicity to evaluate the therapeutic value of our LSR targeting ADCs in syngeneic 4T1 TNBC xenograft models and preclinical patient-derived xenograft TNBC models after surgery and/or chemotherapy. If the anti-cancer efficacy is confirmed in the preclinical models, then it will enhance cytotoxicity to tumor cells with low dose and limit systemic toxicities. Importantly, our proposed work will improve life quality and the survival rate of TNBC patients, especially AA patients, by combining with surgery and/or chemotherapy.